rs587777402

Variant names:

• chr1-63593600-A-T
• rs587777402
• NM_002633.3:c.112A>T

Your query was ambiguous. Multiple possible variants found:

• chr1-63593600-A-T
• chr1-63593600-A-C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM2 PP3_Moderate PP5_Very_Strong

The NM_002633.3(PGM1):​c.112A>T​(p.Asn38Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001386315: Experimental studies have shown that this missense change affects PGM1 function (PMID:25288802)." and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PGM1 NM_002633.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.75
• Publications: 6 publications found

Genes affected

PGM1 (HGNC:8905): (phosphoglucomutase 1) The protein encoded by this gene is an isozyme of phosphoglucomutase (PGM) and belongs to the phosphohexose mutase family. There are several PGM isozymes, which are encoded by different genes and catalyze the transfer of phosphate between the 1 and 6 positions of glucose. In most cell types, this PGM isozyme is predominant, representing about 90% of total PGM activity. In red cells, PGM2 is a major isozyme. This gene is highly polymorphic. Mutations in this gene cause glycogen storage disease type 14. Alternativley spliced transcript variants encoding different isoforms have been identified in this gene.[provided by RefSeq, Mar 2010]

ITGB3BP (HGNC:6157): (integrin subunit beta 3 binding protein) This gene encodes a transcriptional coregulator that binds to and enhances the activity of members of the nuclear receptor families, thyroid hormone receptors and retinoid X receptors. This protein also acts as a corepressor of NF-kappaB-dependent signaling. This protein induces apoptosis in breast cancer cells through a caspase 2-mediated signaling pathway. This protein is also a component of the centromere-specific histone H3 variant nucleosome associated complex (CENP-NAC) and may be involved in mitotic progression by recruiting the histone H3 variant CENP-A to the centromere. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2011]

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001386315: Experimental studies have shown that this missense change affects PGM1 function (PMID: 25288802).; SCV005325043: Published functional studies found this variant is associated with significantly reduced soluble protein expression (PMID: 25288802)
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• PP5: Variant 1-63593600-A-T is Pathogenic according to our data. Variant chr1-63593600-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 133287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002633.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGM1	NM_002633.3	MANE Select	c.112A>T	p.Asn38Tyr	missense	Exon 1 of 11	NP_002624.2
	PGM1	NM_001172819.2		c.-890A>T		upstream_gene	N/A	NP_001166290.1	P36871-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGM1	ENST00000371084.8	TSL:1 MANE Select	c.112A>T	p.Asn38Tyr	missense	Exon 1 of 11	ENSP00000360125.3	P36871-1
	PGM1	ENST00000895883.1		c.112A>T	p.Asn38Tyr	missense	Exon 1 of 12	ENSP00000565942.1
	PGM1	ENST00000650546.1		c.112A>T	p.Asn38Tyr	missense	Exon 1 of 12	ENSP00000497812.1	A0A3B3ITK7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	PGM1-congenital disorder of glycosylation (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	-0.052	T
MutationAssessor	Pathogenic	4.1	H
PhyloP100		8.8
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.76		Gain of phosphorylation at N38 (P = 0.0587)
MVP		0.86
ClinPred		1.0	D
GERP RS		2.6
PromoterAI		-0.066	Neutral
Varity_R		0.98
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587777402; hg19: chr1-64059271;